Review Article

Pediatric heart failure therapy: why β1-receptor blocker, tissue

ACE-I and mineralocorticoid-receptor-blocker?
Sabine Recla1, Dorle Schmidt1, Thushiha Logeswaran1, Anoosh Esmaeili2, Dietmar Schranz1,2
1
Pediatric Heart Center, Justus-Liebig University, Giessen, Germany; 2Department of Pediatric Cardiology, Johann-Wolfgang Goethe University,
Frankfurt, Germany
Contributions: (I) Conception and design: S Recla, D Schranz; (II) Administrative support: All authors; (III) Provision of study material or patients: All
authors; (IV) Collection and assembly of data: S Recla, D Schranz; (V) Data analysis and interpretation: None; (VI) Manuscript writing: All authors;
(VII) Final approval of manuscript: All authors.
Correspondence to: Prof. Dr. Dietmar Schranz. Pediatric Heart Center, Justus-Liebig University, Feulgenstrasse 12, 35385 Giessen, Germany.
Email: Dietmar.Schranz@paediat.med.uni-giessen.de.

Abstract: Pediatric heart failure (HF) treatment lagged behind the knowledge of pharmacological
research and evidence-based clinical experience in adults. Considering the lack of prospective, double
blind randomized studies in children, the review is focused on the preferred indication of specific β1-
adrenoreceptor blockers (ARB), mineralocorticoid antagonists and tissue angiotensin-converting enzyme
inhibitors (ACE-I). Our recommendations are based on the specificity in children, the effectiveness and the
side-effect profile of HF-drugs, the receptor-physiological knowledge and the negative results of the few
pediatric HF studies with an “evidence study label”. In the interest of our pediatric patients, effective HF
treatment has not longer to be postponed by balancing between evidence-based versus pathophysiology-
based approach. At our institution, bisoprolol, lisinopril and spironolactone (BLS) are used treating HF in
patients with left-right shunt lesions, reduced ejection fraction as well as during the inter-stage after HLHS-
Hybrid approach. Chronic use of diuretics and fluid restriction is avoided, if always possible; intravascular
volume deficiency stimulates further the neurohumoral axis. Pediatric HF needs to be treated with a strategy
respecting the variable pathophysiology and the differences of receptor physiology between children and
adult patients. The personalized treatment can be easily proofed by the surrogate parameters as heart rate,
breath pattern, weight gain and image-derived parameters as well as biomarkers. Effective HF-therapy is
also the basis for novel regenerative strategies in particular for young children with “end-stage” HF avoiding
cardiac transplant or death.

Keywords: Pediatric heart failure; β1-receptor blocker; tissue ACE-inhibitor; spironolactone

Submitted Dec 21, 2018. Accepted for publication Mar 28, 2019.
doi: 10.21037/tp.2019.04.08
View this article at: http://dx.doi.org/10.21037/tp.2019.04.08

Definition of heart failure (HF)
HF defines a condition in which the heart is unable
to fulfill the body’s need of blood supply. The reason
of this inability is either known or idiopathic. Cardiac
output is not only a sum of myocardial contractility, heart
frequency, heart rhythm, preload and afterload, but is
also related to contractile synchrony, interventricular
interaction, as well as atrial-ventricular and ventricular-
arterial coupling. Therefore, every single component or
the sum of all components can lead to an insufficient heart
function. Pediatric HF is related to genetic and metabolic
abnormalities, structural diseases with volume or pressure
overload, hypoxemia, arrhythmias or caused by myocardial
disease. Clinical symptoms are dependent on the severity of
HF, but also related to age and the cause of HF (1).
New York Heart Association (NYHA) functional
classification is not suitable to the young pediatric

© Translational Pediatrics. All rights reserved. tp.amegroups.com Transl Pediatr 2019;8(2):127-132

128
population (2). Instead, the Ross classification was
developed related to the symptoms of infants and young
children in term of tachypnea, feeding difficulties, growth
problems, sweating and symptoms of exercise intolerance.
Additionally, the functional class could be correlated to
neurohumoral serum markers as plasma norepinephrine
levels (3).
Pathophysiology
Chronic HF is caused by a progressive disease; the
consecutive symptoms are related to the endogenous
counter-reactions in term of activation of the renin-
angiotensin-aldosterone (RAA) as well as sympathetic
nervous system. Initially, the water-salt retention and
vasoconstriction preserves cardiac output by the Anrep-
effect (4) and the Frank-Starling mechanism (5). In
acute, these mechanisms restore cardiovascular function
with improved symptoms. However, in long-term
sustained activation of the neurohumoral axis worsens LV
remodeling with loss of functional cardiomyocytes and
increased interstitial cardiac fibrosis leading to subsequent
systolic and/or diastolic dysfunction lastly to cardiac
decompensation with secondary end-organ damage (6).
The pathophysiology of the HF in children differs
from that in adults not at least respective to the molecular
regulation. A unique characteristic of pediatric dilated
cardiomyopathy (DCM) is down regulation of both, β1-
AR and of β2-AR, in contrast to DCM in adults where
no change of the β2-AR expression is observed (7).
Further, molecular regulation, including the potentials
of cardiomyocyte proliferation is unique in children;
these mechanisms contribute to postnatal myocardial
growth. Further, it could be shown, that the percentage
of cardiomyocytes in mitosis and cytokinesis is highest
in infancy and the number of cardiomyocytes increases
until an age of 20 years (8). These results suggest an
ability of an age-related myocardial regeneration and a
chance for cardiac proliferation in children and still as an
adolescent, if stimulated (8). Postnatally, also hemodynamic
factors markedly influence myocardial growth; grown-
up of borderline left ventricles are related to the amount
of intracavity blood flow. In general, pressure load led
to both, myocyte hyperplasia/hypertrophy accompanied
by myocardial angiogenesis in contrast to only myocyte
hypertrophy in a later age (9).
© Translational Pediatrics. All rights reserved.
Recla et al. Medical heart failure treatment
Therapy of HF in children
In history, the most important aim of HF therapy was
to improve symptoms, so bedding children in upright
position (10) and treating dyspnea and pulmonary
congestion by diuretics (11). Continuing to the present,
evidence-based clinical trials in children are still missing
and recommendations are predicated on clinician’s
experience. In contrast, HF treatment in adults is based
on guidelines that are periodically reviewed and updated.
These guidelines summarize results from studies of large
cohorts of homogeneous patient groups (12); consecutively,
recommendations are based on multiple randomized
trials with a high level of evidence (level A). Difficulty of
conducting trials with a sufficient number of pediatric
patients result in a lack of evidence-based therapies.
Heterogeneous causes of HF in children in a wide range of
age do not allow recruiting a sufficient number of patients
for randomized trials. Therefore, the few published studies
seem to be underpowered. Moreover, the majority of drugs
used in adult population have not received a regulatory
approval for use in children; 80% of children receive off-
label medications for treating HF (13). Neglecting the
specific pediatric pharmacokinetics and pharmacodynamics,
usually drug levels in children are inadequate or excessive,
when adult doses are scaled on the on children’s body
weight (14). The largest pediatric HF trial utilizing
carvedilol in a multicenter randomized placebo-controlled
trial did not show any treatment effect on the end point
of clinical HF outcomes. The study enrolled 161 children
and adolescents (59% DCM) comparing low- and high-
dose carvedilol therapy to placebo on a background of
conventional therapy (15). In consequence of this and a
few other published results, a recently published Cochrane
review concluded, that there are not enough data to
recommend or discourage the use of β-blockers in children
with HF (16-18). The conclusion, taken only from three
studies with a cohort of 20, 22 and 161 patients, respectively,
might be one reason, that β-blocker are in general less used
by pediatricians. The negative results of the carvedilol study
might have a lot of additional causes as the heterogeneity
of HF in term of etiology and severity, the used dosages
reflecting a strong under-dosing of the utilized β-blocker
and may be the inappropriate use of unselective β-blockers
(Propranolol or Carvedilol) at least treating pediatric DCM.
In context, that infants require in fact fourfold higher doses
of for example carvedilol achieving similar drug exposure to
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Translational Pediatrics, Vol 8, No 2 April 2019
adult patients (19), inappropriate diuretic treatment might
be an additional limiting factor to establish higher and
sufficient dosages of β-blockers, but even ACE-inhibitors.
In fact, the recommended standard pharmacotherapy is
unchanged since more than 20 years and is still consisting
of diuretics, digoxin and usually (70%) an angiotensin
converting enzyme (ACE) inhibitor. Still only 4–18% of
pediatric patients with HF undergo therapy with β-blockers
(20,21). Among these, more than 70% are treated with
carvedilol, despite official FDA reservations considering
carvedilol in children (22). This current prescribing trends
for chronic HF therapy in children might be even called
therapeutic “nihilism” (23).
Child-specific HF therapy
Requirements for specific pediatric HF therapies need to
be based on pathophysiology and distinctive features of
molecular cardiac profile in children. The aim of pediatric
HF-therapy is inhibiting the disease process or creating
a chance for cardiac regeneration, if possible. Therefore,
clinicians have not further to tailor therapeutic strategies
to treat their patient’s symptoms by favoring the triple
D-treatment [diuretics, digitalis, diet (fluid restriction)],
but should provide therapies affecting adverse biological
consequences of sustained neurohormonal activation.
Moreover, an important complementary strategy may be
based on stimulating endogenous regenerative mechanisms.
Considering the research results of Miyamoto
et al. (7), the cardiotoxic effects of endogenously and/
or exogenously stimulated β1-ARs have sufficiently to be
blocked and contrarily, the cardioprotective properties
of β2-ARs be preserved (24); her summary “inhibition of
the already down-regulated β2-ARs may override the benefits
of β1-AR inhibition in children limiting the efficacy of non-
specific blockade in pediatric HF” needs to be taken in account
especially treating HF caused by DCM (7). Rather, β1-AR
inhibition along with β2-AR stimulation could be useful
in acute HF (25,26). Moreover, tachypnea, respiratory
problems and coughing are often first symptoms in
children with HF and hence unselective β-Blockers
may worsen these symptoms, too. The β1- to β2-AR-
affinity of bisoprolol is almost 25 times higher to β1-
AR in comparison to carvedilol (27). This means that
carvedilol needs a much higher dosage for blocking β1-
AR comparing to bisoprolol and contemporary blocks
the β2-AR. Blocking β2-AR means to lose the advantages
of β2-AR preservation in terms of both cardio-protective
© Translational Pediatrics. All rights reserved.
129
properties and side-effects, like bronchoconstriction and
vasodilative effects. Considering the effectiveness of a
drug, obviously it depends on more than just receptor
affinity. As mentioned before, age and disease influence the
pharmacokinetic profile, absorption behavior, metabolism,
tissue distribution and elimination as well as longevity of
action at the given receptors. Regarding of this acquired
knowledge, the selective long-acting β1-Blocker bisoprolol
(B) seems to be the prefers β-Blocker in children with HF,
also in consideration of the parent’s compliance, applicating
the drug only once per day. Combining bisoprolol with the
long-acting tissue angiotensin-converting enzyme (ACE)-
inhibitor as lisinopril, further supports this highly important
aspect of parent’s compliance: both drugs can be applicated
once per day and with a similar dosage of 0.1–0.2 mg/kg
per day (28). Considering that angiotensin II, aldosterone
and catecholamines mediate trophic stimuli at tissue level
and are therefore responsible for the cardiac remodeling,
the β1-blocker bisoprolol has to be combined with an ACE-
Inhibitor and aldosterone-antagonist. ACE-inhibitors have
the properties for reverse remodeling, decreasing systemic
vascular resistance and improvement of vascular compliance.
The remodeling properties seem to be higher especially
with ACE-inhibitors with an effective tissue penetration
like Lisinopril (L) (29,30). Compared to tissue-ACE-I,
high dosages of serum ACE-I, like Captopril, are needed to
inhibit myocardial Angiotensin II formation. High dosages
of serum ACE-I induce furthermore bradykinin-dependent
side-effects, as bronchoconstriction (symptomatic with
cough), especially in young patients. To complete the
neurohormonal blockade, an aldosterone antagonist, like
spironolactone (S), might be additionally used in a low,
non-diuretic dosage, preferentially as an anti-remodeling
drug (31).
Considering an effective anti-congestive treatment by
blocking the sympathetic, RAAS-, and aldosterone system,
overtreatment of diuretics should be avoided and diuretics
should rather be weaned in long-term therapy, if possible.
Inappropriate diuretic treatment forces the neurohumoral
axis because of intravascular and in particular intraarterial
volume depletion; averts also adequate dosages of Beta-
blocker and ACE-I. Additionally, infants with advanced
DCM treated by catecholamines can oftentimes not be
weaned due to overtreatment of diuretics which leads
in some to the inadequate indication for cardiac assist
device. Therefore, in most of the admitted young patients
with advanced DCM, diuretic treatment needs usually
to be weaned, before an adequate B-L-S therapy can
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130 Recla et al. Medical heart failure treatment

Algorithm for pediatric (age!) heart failure therapy (DCM, HFrEF)

Symptoms
at rest
NO may be YES

FC I-II FC II - III FC III - IV

HFmrEF LV-EF <40 LV-EF <35 (despite Inodilator)
LVEDD (z-score >+2) LVEDD >+/– 4.5 LVEDD >+4.5
RV function (RV >45%) RV function (RV >40%) RV function (RV >40%)
HR <110
Admit patient Milrinone
YES NO Start B-L-S start B-L-S
Re-assess If diuretics necessary
consider
Re-assess Start B-L-S rASD*
NO
re-assess Are symptoms
Improved in 48–72 hrs FC IV
normal
LV-EF <25
BNP, sodium
YES age < 5yrs (Inodilator + Catechol)
consider (RV <35%)
Patient discharge rPAB**
close re-assess Consider
“SC-therapy”
“fetal” circulation
Schranz 2018 HTx +/– AD

Figure 1 The figure shows our algorithm of pediatric heart failure (HF) therapy related to the clinical functional class (FC), LV-EF,
LVEDD in relation to the RV-EF (right ventricular ejection fraction). The scheme classifies the severity of heart failure with mid-
range (HFmrEF) and reduced ejection fraction (HFrEF); β-blocker therapy in terms of Bisoprolol, as a highly specific β1-selective AR-
blocker, is recommended in all FC and even considered in infants and young children with FC IV, when catecholamines are continuously
applicated in addition to PDE-3 inhibitors, as Milrinone and/or calcium sensitizer, Levosimendan (Giessen, personal experience, not
proofed in randomized controlled studies). Diuretics as a first line HF-drug is not recommended; patients with FC I and II, diuretics are
usually avoided; favoring adequate dosages of Bisoprolol (B), and the tissue angiotensin-converting inhibitor, Lisinopril (L); the combined
treatment with low-dosed Spironolactone (S) is summarized as B-L-S therapy. FC III, when the indication for diuretics might be indicated
on elevated filling pressures due to left atrial and pulmonary vein congestion, creation of a restrictive atrial septum defect (rASD) should be
considered (32*). In young children (less than 5 years) and in particular infants, a surgically performed reversible pulmonary artery banding
[rPAB; (33**)] is recommended in patients suffering left ventricular dilated cardiomyopathy (LV-DCM) with preserved right ventricular (pRV)
function and the infant or young child is considered for cardiac transplantation (HTx, LVEDD, z-value >+4.5). In case of biventricular
heart failure, resuscitation of a still patent, but constricted ductus arteriosus stenting or a surgical performed reverse Potts shunt should be
considered together with generating a left-right-shunting rASD; further with or without additional bilateral PAB (back to “fetal”, parallel
circulation); the strategy might be severe for bridging to cardiac transplant (HTx), avoiding assist device (AD) or cardiac recovery. BNP,
brain natriuretic peptide; heart rate; SC, stem cell; &, and.

be established. Considering further stimulation of the
neurohumoral axis by inadequate application of diuretics,
the indication for long-term treatment should be strict
and not only based on the diagnosis HF (21). In case of a
real indicated diuretic treatment, FC III–IV creation of a
restrictive interatrial communication should be considered
first and may be preferred over a long-term diuretic
treatment (Figure 1).
Balanced oxygen consumption and delivery (DO 2 =
CaO2 × CO) is sine qua none of an optimized HF therapy;
achieving an adequate hemoglobin level of 12–14 mg/L belongs
to this strategy, but in our opinion also the intermittent
application of the cytokine, erythropoietin. Furthermore,
erythropoietin seems to have cardioprotective effects
beyond of its stimulation of red cell production (34). Known
are also stem-cell mobilization and homing properties
leading to an increase of endothelial progenitor cells (35).
Therefore, we favor erythropoietin as a supportive therapy
in particular in young children with DCM.
Considering the regenerative potential of the
myocardium in children, which is inversely related to the
patients age, all measures favoring regeneration should

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Translational Pediatrics, Vol 8, No 2 April 2019
be considered before cardiac transplantation. In this
context it is important to mention, that the left and the
right heart do not act in isolation. Observing the nature
of congenital heart lesions, the importance of ventricular-
ventricular interaction (VVI) and the role of myocardial
proliferation properties in young children with the chance
for regeneration become obvious (8,36). In fact, VVI plays
a pivotal role for heart function in human beings; the right
and the left heart are strongly linked together sharing a
common ventricular septum, myofibers and pericardium
(36,37). Additionally, as mentioned above, pressure overload
induces myocyte hyperplasia together with angiogenesis
but so far only in young children (9). Based on all of these
observations and gained knowledge, pulmonary artery
banding (PAB) was introduced as a regenerative therapeutic
strategy in infants and young children with advanced
DCM provided for cardiac transplantation (32,33,38,39).
PAB was aimed to restore LV-geometry and synchrony by
leftward shifting of the ventricular septum; VVI-interaction
related preload decrease accompanied with a reduced left
ventricular end-diastolic volume and pressure. Along with
the PAB-induced pressure overload of the right ventricle,
myocyte hyperplasia and hypertrophy are stimulated
providing the endogenous regenerative ability of the
especially young human heart.
Conclusions
Treatment of life-threatening heart insufficiency in children
remains a great challenge. Lacking evidence-based clinical
trials and missing sufficient pediatric guidelines the
therapy remained almost unchanged since decades. One
chance for improvement of pediatric HF therapy might
be achieved by focusing on the current pathophysiological
and pharmacological knowledge. It is hypothesized, that
the target therapy should be based on the selective long-
acting β1-Blocker Bisoprolol, the long-acting tissue ACE-I
Lisinopril and mineralocorticoid-receptor antagonist
Spironolactone (named as BLS-therapy).
Acknowledgements
None.
Footnote
Conflicts of Interest: The authors have no conflicts of interest
to declare.
© Translational Pediatrics. All rights reserved.
131
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Cite this article as: Recla S, Schmidt D, Logeswaran T,
Esmaeili A, Schranz D. Pediatric heart failure therapy: why β1-
receptor blocker, tissue ACE-I and mineralocorticoid-receptor-
blocker? Transl Pediatr 2019;8(2):127-132. doi: 10.21037/
tp.2019.04.08
tp.amegroups.com Transl Pediatr 2019;8(2):127-132